Preventive effect of empagliflozin and ezetimibe on hepatic steatosis in adults and murine models

Background: Even though many oral glucose-lowering or lipid-lowering agents have already been reported to improve hepatic steatosis to some degree, which drug had a more beneficial effect on hepatic steatosis among those drugs has not been precisely explored. We analysed the effect of empagliflozi, a selective sodium-glucose cotransporter 2 inhibitor, and ezetimibe on developing hepatic steatosis. Methods and results: Using 4005,779 patients with type 2 diabetes mellitus (T2DM) or dyslipidemia provided by the Korean National Health Insurance Service (NHIS) between January 2015 and December 2015, we analyzed the odds ratio (OR) of fatty liver development (fatty liver index [FLI] >60). Additionally, we examined the metabolic effects of ezetimibe and empagliflozin in mice fed with a choline-deficient high-fat diet, mimicking the features of human NAFLD. The experiment for agents was performed for the non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH) mouse models independently. In the NHIS data, ORs for the development of fatty liver were significantly lower in all treatment groups than in the reference group, which did not receive ezetimibe or empagliflozin. (Ezetimibe therapy; OR=0.962, empagliflozin therapy; OR=0.527, ezetimibe plus empagliflozin; OR=0.509 compared to reference therapy). Unlike non-alcoholic steatohepatitis mouse model, ezetimibe, empagliflozin, and combination therapy also reduced liver steatosis in the non-alcoholic fatty liver mouse model. Conclusions: Compared with other agents, empagliflozin and/or ezetimibe treatment reduced the risk of developing hepatic steatosis. Our data suggest that empagliflozin or ezetimibe can be primarily considered in type 2 DM or dyslipidemia patients to prevent hepatic steatosis.